Multiple sclerosis is a devastating disease that inflicts sensory, motor and cognitive deficits. Currently, there is no cure and the available therapies have variable results. MS is classically described as a demyelinating disease; however more recent work has demonstrated that much of the irreversible functional loss associated with this disease results from pathology of the nerve cell. Although nerve cell damage is now being investigated, it is primarily studied as a consequence of chronic demyelination. In this proposal, we provide convincing evidence that the nerve cell may be a primary target of the disease. We also present a plausible hypothesis that identifies the cell type that mediates this pathology. Our findings are significant because they will lay the foundation for a better understanding of the disease process and identify novel targets for the development of therapeutic interventions.